Studies in transfusion settings have yielded major insights into the epidemiology, pathogenesis and natural history of HCV infection. Although transmission by transfusion is now rare, U.S. blood centers identify ~10,000 asymptomatic HCV-infected donors each year, contributing substantially to the pool of known infected persons requiring clinical management. The addition of routine HCV RNA testing to HCV antibody screening of all U.S. blood donors in 1999 has enabled both detection of donors in the important viremic, pre-seroconversion phase of primary infection, and discrimination of seropositive donors into presumptive resolved and chronic infections. Blood donation centers are therefore excellent recruitment sites for asymptomatic persons with acute, chronic and resolved community-acquired HCV. Our group, composed of collaborators from the two largest blood donor programs in the U.S. (BSI, ARC) and two major HCV academic centers (UCSF, Johns Hopkins University), is uniquely positioned to study these populations. We propose to: 1) Determine cause-specific morbidity and mortality and medical follow-up and treatment status by mail surveys and death index searches of~10,000 confirmed HCV seropositive blood donors and age-matched controls; 2) Characterize determinants of viral clearance in HCV antibody-positive/RNA-negative donors, and rates of late clearance and recurrent viremia. Donors screened since April 1999 have existing HCV RNA results (and archived donation specimens), identifying them as probable persistent or resolved infections. We will enroll 720 "resolved" and matched "non-resolved" donors into a ease-control study. This will enable us to examine epidemiologic correlates of resolution and persistence, based on survey responses. In addition, we will obtain follow-up specimens to define rates of late resolution or recurrent viremia, and to establish a "resolver repository" of cells and plasma to investigate host genetic and immunologic correlates of clearance. 3) Investigate HCV genetic evolution and cellular immune responses during acute infection in blood donors with resolving versus chronic infections. We will enroll and prospectively follow approximately 25 donors per year who are identified as acutely infected with HCV (RNA-positive/antibody-negative). We will follow these donors monthly for six months. Along with our collaborators, we will study specimens to identify viral and immunologic correlates of resolution during the critical acute infection phase. These investigations will yield important insights into HCV pathogenesis and clarify the natural history of disease for the large number of HCV infected persons identified through donor screening.